This invention concerns materials with chemically induced surface charges for use in augmentation, repair and replacement of both hard and soft mammalian connective tissues. The invention could have direct application to a variety of clinical problems encountered in a number of medical fields, e.g., orthopaedic surgery and maxillofacial surgery.
In the realm of bone surgery there are many osseous defects of diverse etiology, e.g., non-union fractures, bone loss consequent to trauma, malignancy, or infection-induced sequestration, and bone deficits or abnormalities as a result of malformation. Thus, the ability to stimulate formation of bone at specific sites within the skeleton is of considerable clinical importance and a wide array of materials to initiate bone repair and/or to restore or replace missing bone has been examined.
Three major approaches are available to the problem of bone replacement. One is a strictly conformational method whereby defective or missing bone is replaced by an implant (of metal, ceramic or other inorganic material) intended to mimic the form, and optimistically the function, of the missing bone. In the past, this approach has been unsuccessful due to rejection of the material and/or failure of integration of the implant with normal skeletal tissue. More recently, some ceramic materials (hydroxyapatite, tricalcium phosphate) have shown acceptable biocompatability with, and healing in, defect sites with evidence of a direct bond to bone at the interface. These materials, however, lack the mechanical properties of bone, and additionally, bone fails to grow into and become incorporated within the implant. Such materials, then lack the capacity to substitute for natural bone in bone reconstruction.
Alternatively, missing osseous tissue may be substituted for with a matrix which functions as a passive support or scaffold around and into which new bone growth can occur. The matrix attracts, or "turns on", cells that have already been committed to an osteogenic pathway, a process referred to as osteoconduction. Allogeneic bone grafts (banked cadaver bone) succeed exclusively by this mechanism. However, their failure rate, as evidenced by graft loss, sequestration, and delayed healing, is unacceptably high (15-30%). Even when such grafts are well accepted, their healing periods for consolidation and capacity for mechanical stress-bearing are of long duration when compared to autogeneic bone grafting. Further, the present concern about transmissible viral agents, coupled with unfulfilled clinical expectations, has led to limited use of allogeneic grafts at present.
The third approach to bone replacement, involving osteoinduction, occurs when a material or substance induces the ingrowth of new bone from the host's undifferentiated tissues, typically around a temporary matrix. Such material is termed osteoinductive and a number of compounds have been shown to have such a capacity and are enumerated in detail in U.S. Pat. No. 4,440,750 to Glowacki. At present, the most promising of these factors has been "bone morphogenic protein" (BMP) which was extracted from demineralized bone using urea or guanidine hydrochloride and re-precipitated according to the disclosures in U.S. Pat. Nos. 4,294,753 and 4,455,256 to Urist. In addition, U.S. Pat. Nos. 4,434,094 and 4,627,982 to Seyedin and Thomas, respectively, report a substance termed "osteogenic factor" which appears to be a bone generation-stimulating, bone-derived protein. While substances such as these stimulate osteogenesis, the difficulty in using such a protein, or proteins, is that they are normally present at very low concentrations and require large amounts of starting material to obtain sufficient quantities for a few experiments let alone as a routine reagent for bone repair. Until molecular technology identifies the gene or genes for such factors, and recombinant molecules are obtained, the practicality of this approach is of limited clinical value.
Collagen-based solutions, which polymerize after injection or placement (U.S. Pat. Nos. 4,424,208 to Wallace and 4,347,234 to Wahlig), have also been described in U.S. Pat. No. 3,949,073 to Daniels for hard tissue augmentation. In addition, Hollinger, in U.S. Pat. No. 4,578,384, describeds a proteolipid incorporated into a biodegradable polymeric matrix comprised of a 50-50 polyacetic acid (PLA) and polyglycolic acid (PGA) for the healing of osseous tissue. The use of collagen-based polymers, however, presents several problems. Collagen, although generally biocompatible, is not completely biodegradable or resorbable and often becomes surrounded, and not absorbed, by host tissues. As such, when placed in a bone bed, where rigidity is ultimately desired, it represents a potential source of long-term mechanical failure. Additionally, collagen, being an organic substance most commonly commercially derived from bovines, allows for the possibility of allergic and immune reactions.
Thus, many of the criteria for an acceptable material for bone repair remain unsatisfied with present methodology. A replacement compound that is immunologically acceptable, nontoxic, osteoconductive or osteoinductive, readily available, capable of being shaped or molded, and capable of being integrated with existing bone tissues continues to be sought.
As with bone or hard tissue, the promise of alloplastic biomaterials that are effective in promoting or enhancing soft connective tissue repair and/or augmentation has not been fully realized. Silicone (dimethylpolysiloxane), introduced in 1964, was initially widely used because of its purported lack of absorption. Extensive clinical experience has shown, however, that an unacceptable number of complications, including granulomatous inflammatory changes, migration of the implant material, and chronic erythema of the overlying skin occur and, as a result, this material has never received FDA approval. Collagen in the commercial form of Zyderm and Zyplast (manufactured by Collagen Corp., Palo Alto, Calif.), introduced in 1979, has met with more encouraging results. It has proved effective, without significant side effects, in the adjunctive management of the aging face as well as in the primary treatment of small cutaneous defects from acne, trauma, or prior surgery. However, it is not permanent and repeated treatments are usually necessary to maintain correction. Thus, it is of little use for stimulating connective tissue production and the laying down of new tissue. It is, rather, an inert dermal filler which is shortly resorbed. In addition, because the material is of bovine origin, allergic and immune reactions can occur and are not rare phenomena. Lastly, the use of collagen is presently limited to small deficiencies and has no proven efficacy in large defects (requiring more than 5 cc of material). As such, collagen represents an improved, but limited, material for soft tissue repair and augmentation.
More recently, with the introduction of Fibrel (manufactured by Serono Laboratories, Inc., Randolph, Mass.) in 1987, there was a new type of soft tissue material which could stimulate connective tissue production rather than inertly fill space. Fibrel is a commercial form of a combination of collagen, gelatin, and epsilon aminocaproic acid which, most likely, acts like a reservoir for growth factors which are in high concentrations in coagulum around the collagen base. Early studies suggest that volume maintenance is prolonged but permanency is still not achieved. Furthermore, the inherent risks of bovine collagen, as previously mentioned, remain.
Thus, improved methodologies and diferent biologic approaches continue to be warranted in the search for materials to effect both hard and soft connective tissue repair and augmentation.